As the proportion of elderly individuals in the United States rises, the burden of age-associated disease grows. Aging is a universal feature of eukaryotic organisms, yet the molecular mechanisms underlying aging remain largely obscure. A detailed molecular understanding of aging might allow the delay or prevention of aging-associated deterioration and perhaps the extension of human lifespan. Overexpression of Sir2 family members has been shown to extend lifespan in both yeast and C. elegans, and overexpression of a mammalian Sir2 family member, SIRT1, increases oxidative stress resistance in mammalian cells. This protein also can deacetylate p53, reducing p53 activity. The overall goal of this proposal is to define the role of Sir2 family members in stress resistance, modulation of p53 activity, and aging. This analysis will be performed in mice, and entails three specific aims. (1) To define which of the murine Sir2 family members are involved in oxidative stress resistance, and to determine whether overexpression of Sir2 proteins in mice can extend murine lifespan. (2) To evaluate the genetic interaction between SIRT1 and p53. (3) To define the role of Sir2 family members in the maintenance of chromosomal stability. This application is for a Mentored Clinical Scientist Development Award (K08). The applicant is an M.D. /Ph.D. with a longstanding interest in the basic biology of aging, and residency training in Anatomic Pathology. The proposed research will take place in the laboratory of Dr. Frederick AIt at the Center for Blood Research at Harvard Medical School. The applicant previously trained in a laboratory specializing in yeast. The candidate's long-term goal is to direct an academic research group investigating the molecular mechanisms of aging and interventions to delay the onset of senescence. This training grant would serve as a critical bridge to this independent position, by allowing the candidate to study in one of the foremost mammalian labs in the country.